1. Field of the Invention
The present invention relates to novel compounds having inhibitory activity against the biosynthesis of triglycerides and inhibitory activity against the secretion of apolipoprotein B-containing lipoproteins, and pharmaceuticals comprising the compounds as an active component, especially prophylactic or therapeutic agents for hyperlipidemia.
2. Background Art
A change in dietary habits and an increase in population of persons of advanced age has lead to an increase in arteriosclerotic diseases. An abnormal increase in the level of cholesterol and triglycerides which are serum lipids (hyperlipidemia) may be one major risk factor of this group of diseases. For example, the proportion of patients suffering from familial combined hyperlipidemia (FCHL) among patients suffering from cardiac infarction is about 30%, which is a higher frequency than the case of other underlying diseases. Furthermore, the familial combined hyperlipidemia (FCHL) is known as an underlying disease which has a high risk of onset of ischemic hear diseases (Lipid, 2, 373 (1991)).
Hyperlipidemia, which takes place with high frequency as the complication of obesity and diabetes mellitus, is also recognized as a risk factor of arteriosclerosis (Diabetes, 37, 1595 (1988) and Int. J. Obesity, 15, 1 (1991)).
Further, it is also known that among hyperlipidemia, hypertriglyceridemia leads to pancreatitis and the like (Medical Practice, 12, 957 (1995)).
Therefore, the treatment of hyperlipidemia is important for the prevention and treatment of arteriosclerotic diseases, such as ischemic hear diseases and cerebrovascular diseases. Further, it has been pointed out that there is a possibility that hyperlipidemia attended with renal diseases evolves the renal disorder (Molecular Medicine, 31, 536 (1994)). For this reason, the necessity of treating hyperlipidemia has been proposed.
For the treatment or prevention of hyperlipidemia and arteriosclerotic diseases, statin compounds, such as Lovastatin, as agents for inhibiting the biosynthesis of cholesterol, particularly as agents for inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and fibrate compounds, such as Bezafibrate, as agents for lowering the level of triglycerides, have been clinically used as pharmaceuticals.
Further, in recent years, reducing the level of triglycerides in serum and the level of apolipoprotein B-containing lipoprotein in serum, which is considered to induce arteriosclerosis, is expected to be useful for the prevention and treatment of the above diseases (Arterioscler. Thromb., 12, 1284 (1992) and Circulation, 85, 37 (1992)). One reason for this is that patients suffering from abetalipoproteinemia, in which apolipoprotein B-containing lipoprotein is not detected in blood, do not cause arteriosclerosis (Clin. Chem., 34, B9-12 (1988)).
Compounds known to have such activity include pyrrolecarboxylic acid derivatives, sulfonamide derivatives, phenylpiperazine derivatives, and biphenyl-2-carboxylic acid derivatives. Further, isoindolone derivatives having a substituent only in the nitrogen atom at the 2-position are also known (EP 643057 and WO 96/26205).
On the other hand, compounds having piperazine on the benzene ring in isoindolone and isoquinolone skeletons are known (WO 96/26187). These compounds, however, are different from the compounds of the present invention in the substituent of nitrogen at the 2-position and, in addition, acts as fibrinogen receptor antagonist. Thus, the above compounds are different from the compounds of the present invention in idea.
The present inventors have previously disclosed, in WO 98/54135, compounds which have piperazine on a benzene ring of isoindolone and isoquinolone skeletons and inhibit the secretion of apolipoprotain B-containing lipoprotein.
On the other hand, benzamide compounds are not known which have piperazine on a benzene ring and have two substituents other than a hydrogen atom on a nitrogen atom and, at the same time, inhibit the biosynthesis of triglycerides and inhibit the secretion of apolipoprotain B-containing lipoprotein.
Further, compounds having piperazine on a naphthyridinone skeleton are not also known. Furthermore, compounds are also not known which have piperazine on a pyridine skeleton and, in addition, have an N,N-di-substituted carbamoyl group.
Furthermore, compounds are not also known which have piperazine on naphthyridinone and pyridine skeletons and inhibit the secretion of apolipoprotein B-containing lipoproteins.
Agents, which have the activity of lowering serum triglyceride level and have the activity of lowering blood apolipoprotein B-containing lipoprotein level based on a new mechanism of action and, at the same time, do not cause, as side effect, the accumulation of some lipids within the liver which is found in abetalipoproteinemia, have been desired to be developed as prophylactic or therapeutic agents for hyperlipidemia or arteriosclerotic diseases (The Metabolic Basis of Inherited Disease, Sixth Edition, 1139 (1989)).